Chun-Jen Liu, MD, PhD
Dual infection with hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is not rare in either virus endemic areas. In patients dually infected with both viruses, the disease outcomes are usually more severe than those with HBV or HCV monoinfection. For dually infected patients with active hepatitis C, combined pegylated interferon alfa plus ribavirin therapy was effective. During post-treatment follow-up, the HCV response was sustained in 97% of patients. Moreover, the long-term outcomes including the development of HCC and liver-related mortality were improved. However, the optimal treatment strategies for dually infected patients with active hepatitis B or established cirrhosis remain unknown. Finally, the role of new direct-acting antiviral (DAA)-based therapy for the treatment of patients with dual HCV/HBV infection also remains to be explored in future clinical trials.
Usually, patients have chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) monoinfection. However, in areas or countries where hepatitis B virus (HBV) infection is endemic or among subjects at risk of parenteral viral transmission, it is not uncommon to encounter patients infected with both hepatitis B and C viruses 1-3. Previous studies already clarified the following issues regarding dual HCV/HBV infection. First of all, in patients co-infected with hepatitis C and B, the disease manifestations are usually more severe than those with mono infection 4-7. Furthermore, it is important to select the priority virus to be treated in patients with dual chronic hepatitis C/B by chronologically monitoring the viral activity of either one. In dually infected patients with active hepatitis C, pegylated interferon (Peg-IFN) alfa plus ribavirin (RBV) was effective to achieve HCV RNA sustained virologic response (SVR)8; and the durability of HCV SVR was maintained in 97% during post-treatment 5-year follow-up study 9. Moreover, using Peg-IFN-based therapy, HBsAg seroclearance was documented in 5.4% of dually infected patients per year. Finally, apart from the short-term control of viral infection, a population-based study has demonstrated that the use of Peg-IFN plus RBV combination therapy significantly reduced the risk of hepatocellular carcinoma (HCC) development, liver-related mortality, and all-cause mortality 10.
Several hospital or community-based studies demonstrated that in patients co-infected with chronic hepatitis C and B, the disease outcomes are usually worse than those with either chronic HCV or HBV infection 1-7. Patients with HCV/HBV co-infection may exhibit various fluctuating virological profiles; basically HCV and HBV can alternate their dominance during long-term follow-up. In Italy, a longitudinal follow-up study revealed the patterns and dynamics of virological dominance in these cases 11. Of 103 untreated HBV/HCV coinfected patients, active infection with HBV and HCV was revealed in 24 (23%) cases, inactive infection of both viruses was seen in 15 (15%) cases, active HBV and inactive HCV infection was seen in 15 (15%) cases, and active HCV and inactive HBV infection was found in 49 (48%) cases. During one year follow-up, fluctuation of HBV and/or HCV viremia levels was documented in 32 subjects (31%). Based on these findings, careful evaluation of serum HBV DNA and HCV RNA levels is essential before the diagnosis of the viral dominance which will influence the therapeutic strategies in the co-infected patients.
Active hepatitis C is found in at least 50% of dually infected patients 11. Moreover, HCV can be successfully eradicated in at least 50% of patients with chronic HCV mono-infection using combination therapy of Peg-IFN and RBV worldwide 3. Therefore, HCV seems to be the priority target to be managed in dually infected patients with active hepatitis C.
In the treatment of patients with HCV mono-infection, Peg-IFN in combination with RBV remains the standard of care in many Asian Pacific countries. Our multicenter trial data demonstrated the efficacy of treatment of dually infected patients through Peg-IFN plus RBV 8: for genotype 1 infection, HCV SVR rate was 72.2% in dually infected patients and was 77.3% in mono-infected patients; for genotype 2/3 infections, SVR rate was 82.8% in dually infected patients and 84.0% in mono-infected patients.
Durability of HCV responses post-treatment
Hepatitis C virus may reappear in 0.9~10% of chronic hepatitis C mono-infected patients achieving initial HCV SVR. To clarify this issue, the durability of HCV SVR in the dually infected patients was investigated by a 5-year follow-up study 9. Our results revealed that after a median follow-up of 4.6± 1.0 years, only 6 (2.6%) of the 232 patients achieving SVR developed HCV RNA reappearance. Our data suggested that the HCV SVR was durable in dually infected patients receiving Peg-IFN alfa and ribavirin combination therapy.
Clearance of HBsA and HBV reactivation
HBsAg clearance at 6 months after end of therapy was found in 18 (11.2%) of the 161 dually infected patients. During 5-year post-treatment follow-up, the rate of HBsAg seroclearance was 5.4% per year, reaching 30% at the end of follow-up 9,12.
Potential risk for reactivation of HBV DNA during or after treatment of chronic hepatitis C is a major clinical concern for in HCV/HBV dually infected patients 2. In our treatment cohort of 76 patients with pretreatment serum HBV DNA <200 IU/mL, reappearance of HBV DNA was found in 47 (61.8%) patients 9. Therefore these patients should be monitored regularly and prompt anti-HBV therapy should be implemented if clinically indicated.
Improvement of long-term outcomes post-treatment
Whether Peg-IFN and ribavirin combination therapy could reduce the risk of HCC or improve survival in HCV/ HBV dually infected patients was evaluated in a large population-based cohort from Taiwan 10. We examined the risk of HCC, mortality, and adverse events in 1,096 treated and 17,562 untreated HCV/HBV dually infected patients. After adjustment, combination therapy significantly reduced the risk of HCC (hazard ratio [HR] 0.75, 95% confidence interval [95%CI] 0.58–0.96), liver-related mortality (HR 0.45, 95% CI 0.35–0.57), and all-cause mortality (HR 0.39, 95%CI 0.32–0.48). Nevertheless, the underlying HBV infection was still a risk factor for HCC and mortality after treatment. Our data demonstrated that combination therapy in addition to control of HCV activity in the short-term, also decreased the risk of developing HCC and improved survival in HCV/HBV dually infected patients 10.
HCV and HBV co-infection is not uncommon in areas endemic for HBV infection and among subjects at risk of parenteral transmission. Thorough serological and virological examinations are required to determine the viral dominance as well as to determine the optimal antiviral regimen before the start of anti-viral therapy. For dually infected patients with active hepatitis C, genotype-dependent treatment recommendations for single chronic hepatitis C can be applied 13-15. However, for dually infected patients with active hepatitis B or with established cirrhosis, the optimal regimens await further studies. The clinical application of new DAA-based triple therapy in this population also remains to be clarified.